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A PI3KCA inhibitor reverses symptoms in a mouse model of PROS/CLOVES syndrome, which results from gain-of-function mutations in PI3KCA, and produces improvements in patients with PROS/CLOVES syndrome.

In this study, the authors generate a new mouse model that allows selective genetic targeting of microglial cells. Using this model, they show that elimination of TGF-β-activated kinase 1 (TAK1) specifically in microglial cells reduces pathology in a mouse model of multiple sclerosis by inhibiting NF-κB, ERK and JNK signaling pathways.

The role of vascular plasticity in brain function remains poorly understood. Here, the authors demonstrate that a significant portion of blood vessels in the adult brain periodically occlude and regress, a process that is associated with a reduction in neuronal activity.

Hachem et al. show that AMPAR signaling drives the acute activation of ependymal-derived neural stem/progenitor cells after spinal cord injury and that this mechanism can be targeted therapeutically to harness the endogenous regenerative potential of the spinal cord.

Previously undescribed hierarchical arrangements in haematopoietic stem cells and their niches that mediate both regenerative potential and immune privilege are identified.

Yahara et al. show that yolk-sac macrophages, which are derived from erythromyeloid progenitors, produce neonatal osteoclasts that support bone homeostasis and repair and also provide long-lasting osteoclasts in adult bone.

The authors show that aberrant epithelial GREM1 expression remodels intestinal stroma to form ectopic stem cell niches in mice. Anti-GREM1 reversed these changes, highlighting a potential strategy for preventing polyposis in patients with HMPS.

The peripheral nervous system has been implicated in wound healing. Here, Parfejevs and colleagues report that cutaneous wounding in mice induces the de-differentiation and proliferation of Schwann cells, which disseminate into the wound bed, secrete soluble factors, and promote wound healing.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

Isolating tissue-resident cells runs the risk of altering their expression profile. Jung and colleagues use a RiboTagging approach to describe the microglial translatome and demonstrate that macrophage extraction from their tissue environment results in significant transcriptional alterations.

Microglia and border-associated macrophages play a role in regulating cerebral blood flow (CBF), but the underlying mechanisms are unclear. Here, the authors show a role for microglial CD39 in the regulation of basal CBF and neurovascular coupling.

Distinct cortical pyramidal neuron types, defined by developmental lineage, make unique contributions to behavioral decisions. We highlight the importance of interactions among diverse cortical and subcortical areas for successful decision outcomes.

This study shows that pyramidal tract (PT) and intratelencephalic (IT) projection neurons process information via distinct parallel subnetworks across cortex, each preferentially associated with either motor events or sensorimotor transformation.

Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.

Analysis of macrophage subsets within joints reveals a population of CX₃CR1⁺ tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells.

Adult neural stem and progenitor cells (NSPCs) show high levels of fatty acid synthase (Fasn)-dependent de novo lipogenesis, a process that is controlled by Spot14 to regulate the rate of proliferation; this indicates a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.

IgA-secreting plasma cells that originate in the intestine are found in the meninges, where they protect the brain against pathogens.

The authors report a mechanistic basis for intestinal polyp formation in patients with hereditary mixed polyposis syndrome that involves the aberrant epithelial expression of morphogens and leads to the formation of ectopic intestinal crypts by progenitor cells outside the stem cell niche, a mechanism that seems to also be involved in human ectopic serrated polyps.

DNA methylation and copy number variant analyses across a large number of genetic mouse models of pediatric brain tumors reveal subtype-specific molecular alterations shared with the corresponding human diseases.

Glial cells and their crosstalk after injury are crucial for brain regeneration. Here, the authors show the spatial, temporal, and single-cell responses of glial cells after injury and identify shared pathways controlling glial reactivity.

Rinkevich and colleagues show that preexisting matrix is transferred by neutrophils across organs into injured sites in a manner dependent on integrin activation.

Leushacke et al. provide insights into the role of Lgr5 cells in the oxyntic stomach, demonstrating that they label a subpopulation of chief cells that function as reserve stem cells during regeneration and cells-of-origin of gastric cancer.

Huebner et al. develop a 2D culture system to study gastric isthmus stem cells and identify a role for Sox2 in specifying enterochromaffin cells in the stomach.

Recent developments in sequencing technologies have provided the opportunity to investigate the biodiversity of ecosystems. Such a metagenomic approach, combined with taxon clustering, is used here to demonstrate that the species richness of a marine community in Scotland is much greater than anticipated.

The transcription factor PU.1 is an essential regulator of the pro-fibrotic gene expression program in fibroblasts; PU.1 expression is upregulated in various fibrotic diseases, whereas inactivation of PU.1 induces regression of fibrosis in a number of organs.

The neuropeptide CRH is believed to induce aversive, stress-like behavioral responses. Here the authors describe a distinct population of CRH neurons in the extended amygdala that act to suppress anxiety by positively modulating dopamine release.

Three-photon in vivo imaging provides access to medial prefrontal cortex, hippocampus and spinal cord in mice at up to 1.7 mm depth of neurons, dendrites, spines, astrocytes and microglia.

Loss of let-7, a key microRNA, causes lung alveolar stem cells to grow abnormally and dieprematurely, leading to scarring and lung damage. Here the study links let-7 loss to cancer-like signals and epigenomic gene changes, revealing new treatment paths for lung fibrosis.

A large literature has demonstrated the important role of spinal microglia in chronic pain processing. This paper demonstrates that microglia are required in male but not female mice. In female mice, a similar function appears to be subserved by adaptive immune cell, likely T lymphocytes.

CD98hc in macrophages attenuates the severity of colitis. This change in the macrophage development is associated with increased expression of apoptotic genes, suggesting that CD98hc maintains the gut homeostasis by ensuring the development of gut macrophages.

Lysosomes maintain RPE health via TFEB/E3-regulated autophagy. Here, the authors show deregulated AKT2/SIRT5/TFEB signaling in the RPE inhibits both lysosomal and mitochondrial function and leads to AMD, suggesting this pathway might provide a therapeutic target for AMD.

Analysis of colorectal cancer bulk gene expression data at the pathway level identifies a poor-prognosis subtype associated with cell differentiation. The subtypes are reproducible in single-cell data and offer biological insights beyond existing stratification strategies.

Chronic viral infection leads to a dysregulation of germinal center B cell responses. Di Pietro et al. show that the epigenetic modifier BMI-1 promotes this dysfunctional response and that targeting BMI-1 in B cells can restore humoral immunity and accelerate viral clearance.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

In this study, Vande Voorde et al. investigate the potential of untargeted metabolomics as a stratification tool for colorectal cancer (CRC). They present a comprehensive pipeline to uncover metabolic vulnerabilities in CRC based on its genetic origin. With this approach, they show perturbations in methionine metabolism linked to APC deficiency, and identify adenosylhomocysteinase as an actionable therapeutic target.

Safaiyan et al. demonstrate that myelin fragments progressively pinch off from aged myelin sheaths and are taken up and cleared by microglia. Age-associated myelin breakdown is substantial and saturates the degradative capacities of microglia, leading to lysosomal storage and an immune activation in microglia with time.

Using intensive eDNA sampling in space and time across five rivers in Europe and North America, this study shows that eDNA gives relevant information on freshwater diversity and ecology across broad taxonomic groups, and with limited downstream transport. The findings demonstrate that eDNA is vital for freshwater biodiversity monitoring in a time of anthropogenic change.

Chemical genetic dissection of the SWI/SNF–Polycomb axis in mouse stem cells identifies an unexpected role for mSWI/SNF in repression, providing mechanistic insight into the dynamic ‘tug of war’ between transcriptional activation and repression.

Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death. Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.

The identification of mRNA targets for RNA binding proteins (RBP) in stem cells is difficult due to the limited number of available cells. Here, as a proof-of-principle, the authors adapt the HyperTRIBE method to find that an RBP, MSI2, has increased RNA binding in leukemic compared with normal stem cells for selective regulation of oncogenic genes.

Using a globally distributed standardized aerial sampling of fungal spores, we show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude.

Although mutant H3K27M histones inhibit PRC2 in diffuse intrinsic pontine gliomas, these tumors exhibit significant amounts of PRC2 activity. The repression of several genes, including INK4A, by residual EZH2 activity is required for tumor growth, and EZH2 inhibitors therefore represent potential therapies for these patients.

Roquin is an RNA-binding protein that promotes the degradation of specific mRNAs and is crucial for the maintenance of peripheral immune tolerance. Here the authors show that, in addition to its target mRNAs, Roquin can bind miR-146a and the RISC component Ago2 to control homeostasis of both RNA species.

Lysine hydroxylation of procollagen precursors by LH3 is required for collagen fibril crosslinking and stabilization. Here the authors show that the trafficking protein VIPAR is required for correct sorting of LH3 into post-Golgi collagen carriers and for correct collagen modification and structure.

The myogenic determinant Pax7 is thought to have a critical role in adult muscle stem cells (satellite cells), but a formal demonstration has been lacking in vivo. Here it is shown that, unexpectedly, when Pax7 is inactivated in adult mice, mutant satellite cells are not compromised in muscle regeneration. Multiple time points of gene inactivation reveal that Pax7 is only required up to the juvenile period, indicating an age-dependent change in the genetic requirement for muscle stem cells.

DNA metabarcoding is used to survey the spatial and temporal distribution of airborne grass pollen genera over the summer grass pollen season across Great Britain.

Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death.